Fast-acting analgesic

ABSTRACT

A fast-acting analgesic comprises as analgesic substance ibuprofen in an adjuvant matrix with a porous structure and a density of greater than 1 and up to 2.5 g/cm 3 .

The present invention relates to a fast-acting analgesic preparationcomprising as analgesic substance ibuprofen in an adjuvant matrix, wherethe preparation has a porous structure and a density of greater than 1and up to 2.5 g/cm³.

The invention furthermore relates to a process for producing thepreparation.

The use of ibuprofen, 2-(4-isobutylphenyl)propionic acid, asnonsteroidal analgesic has been known for a relatively long time.Ibuprofen has an asymmetric carbon atom and, in the form usedtherapeutically, is generally in the form of the racemate.

The low solubility of the active substance is a problem with regard tothe rapid onset of action which is required in the treatment of pain.

DE-C 36 39 038 discloses the achievement of a faster onset of action byusing the pure S(+) isomer.

DE-C 41 40 185 proposes solving the problem of the low solubility ofibuprofen by using colloidal dispersion systems based on gelatin.

The problem of low solubility is furthermore frequently solved byconverting ibuprofen into its water-soluble salts. However, sodiumibuprofenate, for example, is hygroscopic and can be tableted onlypoorly.

Ibuprofen is also available as lysine salt which, compared with the freeacid, achieves a distinctly faster and higher maximum blood levelC_(max) and is currently regarded as the fastest dosage form. However,the conversion of the acid into the salt is more elaborate and morecostly. In addition, lysine has, as amino acid, an allergenic potential,which is why the lysine salt has not been approved as medicinal productin some countries.

WO 96/29061 describes the production of transparent solid solutions ofibuprofen salts by a melt extrusion process.

It is an object of the present invention to find a fast-actingpreparation of ibuprofen which achieves an effect which is as good asthat of the lysine salt.

We have found that this object is achieved by the preparation defined atthe outset, and a process for producing it.

Ibuprofen is processed according to the invention as free acid,preferably in the form of the racemate. However, it is also possible touse S(+)-ibuprofen. Depending on the dosage, the preparations maycomprise from 5 to 80, preferably from 20 to 60, % by weight ofibuprofen. Suitable dosages are, for example, 200 mg or 400 mg per drugform. The active ingredient is preferably in the form of solid solutionin an adjuvant matrix. The term “solid solution” is known to the skilledworker (cf. Chiou and Riegelmann, J. Pharm. Sci. 60(9), (1971)1281-1301).

Besides water-soluble polymeric binders, the adjuvant matrix comprisescarbonates and, where appropriate, conventional pharmaceuticaladjuvants. Water-soluble means that at least 0.5 g, preferably at least2 g of the polymer dissolve, where appropriate colloidally, in 100 g ofwater at 20° C.

Suitable polymeric binders according to the invention are water-solublecellulose derivatives such as hydroxyalkylcelluloses, for examplehydroxypropylcellulose, and, in particular, water-soluble homo- andcopolymers of N-vinylpyrrolidone (NVP) with K values in the range from10 to 90, preferably K25 to K30. Examples of suitable copolymers arecopolymers of NVP and vinyl acetate, for example a copolymer of 60% byweight NVP and 40% by weight vinyl acetate with a K value of 28 or 30.Polyvinylpyrrolidone (PVP) with a K value of 30 is particularlypreferred as polymeric binder (for determination of the K value, see H.Fikentscher, Cellulosechemie 13 (1932) 58-64 and 71-74). It is alsopossible to employ mixtures of binders. The polymeric binders can beemployed in amounts of from 10 to 80, preferably 30 to 70, % of thetotal weight of the preparation.

Suitable carbonates according to the invention are the alkali metalcarbonates sodium carbonate and potassium carbonate, and the alkalineearth metal carbonates calcium carbonate and magnesium carbonate. Alsosuitable furthermore are the corresponding bicarbonates of sodium andpotassium.

The carbonates or bicarbonates can be employed in amounts of from 0.1 to20, preferably 2 to 15, % of the total weight of the preparation.Anhydrous carbonates or bicarbonates are preferably employed. It is alsoparticularly preferred to employ ground carbonates, in which case theparticle sizes are preferably less than 500 μm.

The preparations may additionally also contain conventionalpharmaceutical adjuvants in the amounts customary for this purpose, forexample stabilizers, antioxidants, dyes, flavorings, bulking agents orstabilizers such as highly disperse silica or lubricants. The drug formsmay furthermore also comprise codeine, caffeine or vitamin C in theamounts customary for this purpose.

The preparations according to the invention are produced by mixing thecomponents using shear forces and supplying thermal energy. The mixingpreferably takes place in a single-screw or multiscrew extruder,particularly preferably a twin-screw extruder. The supply of thermalenergy produces a melt of the mixing components. This normally takesplace by heating the extruder jacket to from 50 to 180, preferably 80 to130° C. The active ingredient can be mixed with the other componentsbefore or after the melting of the polymeric binder. The melts aresolvent-free. This means that no water or organic solvents are added.

The molten mixture of the components is conveyed by the screw movementtoward the extruder outlet, which preferably consists of a die. Thepressure is reduced to from 10 to 600 mbar, preferably 30 to 200 mbar,particularly preferably 50 to 150 mbar, according to the invention inthe last segment or section before the die. After extrusion through thedie, the still plastic composition is shaped to suitable drug forms.

Suitable drug forms are preferably tablets, for example bolus tablets,lenticular tablets or else buccal tablets, pastilles, instant granules,granules or pellets for sachets or for filling capsules. Suppositoriesare also suitable according to the invention.

Tablets are preferably produced by the process described in EP-A 240 906by passing the still plastic extrudate between two rolls which aredriven in opposite directions and have mutually facing depressions inthe surface of the rolls. It is also possible to obtain tablets withscores by appropriate choice of the shape of these depressions. Granulesor pellets can be obtained by cold cutting or, preferably, by hotcutting.

The drug forms may additionally be provided with coatings known per sewhich have no effect on the release behavior.

The drug forms according to the invention are suitable for the preferredoral administration. They have a density, determined using a heliumpycnometer, of more than 1 and up to 2.5, preferably from 1.1 to 2.0,particularly preferably from 1.4 to 1.9, g/cm³ and are porous. Thedensity is determined using a helium pycnometer in accordance with OECDGuideline, Paris 1981, Test Guideline, page 100, or according to DIN55990 or DIN 53243. This entails determination of the volume of liquidhelium displaced. In contrast to conventional methods, this procedureprovides the true density of a solid and not the apparent density. Thehelium is able, because of its small atomic diameter, to penetrate intothe smallest fissures and pores.

The average pore size is preferably 80 μm, and the pores may havediameters of from 10 to 300 μm. A honeycomb-like structure is evident inthe cross section through a drug form.

The active ingredient is particularly preferably present as solidsolution in the matrix, which can be demonstrated by DSC measurements(Differential Scanning Calorimetry) and by X-ray diffractioninvestigations. The drug forms may, however, also be present as mixedforms in which part of the active ingredient is in the form of a solidsolution and another part is recrystallized. The active ingredient canalso be in completely recrystallized form. The proportion ofrecrystallized free acid can be controlled by the amount of carbonateadded.

In contrast to known solid solutions of ibuprofen, the drug formsaccording to the invention are, however, not transparent but have anopaque appearance.

The release rate for the active ingredient by the USP23 rotating basketmethod is at least 95% after 10 min.

The preparations according to the invention show not only rapid releasebut also a rapid action. The time (t_(max)) until the maximum bloodplasma level (C_(max)) is reached is in the region of 0.5 hour.

The AUCs (areas under the concentration-time curves), which are ameasure of the amount of substance in the body, for the drug formsaccording to the invention are substantially comparable with those for acommercial fast-acting ibuprofen lysinate.

In view of the prior art, it was completely surprising that the drugforms according to the invention are bioequivalent to the lysinates.

It was also surprising that porous forms with a density of greater than1 g/cm³ were obtained by reducing the pressure before the extruderoutlet.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph plotting blood plasma concentration over time.

EXAMPLES

The compositions indicated in each of the following examples werepremixed and introduced into the feed section of a twin-screw extruder(ZSK-40, Werner & Pfleiderer). Extrusion took place with a productthroughput of 25 kg per hour at a screw speed of 90 rpm. Thetemperatures in the individual zones (sections) of the extruder and theheated die strip were:

section 1: 80° C., section 2: 120° C., section 3: 130° C., section 4:130° C., head: 130° C., die 130° C. The pressure in section 4 was 51.5mbar. Bolus tablets were produced from the extrudate by the calenderingprocess described in EP-A 240 906.

The release of active ingredient was measured by the USPXXIII basketmethod. Determination takes place at 37° C. in a no-change test at a pHof 7.2 and at 150 rpm. The test medium employed was a 0.05 molar aqueouspotassium dihydrogen phosphate solution which had been adjusted to pH7.2 with sodium hydroxide solution. An appropriate amount of drug formwas weighed out. The assay was carried out photometrically by means of aderivative spectrum at 256 to 270 nm with external standard calibration.

The tablets were provided with a commercially obtainable coating(Opadry® OY-S-24939 supplied by Colorcon), a 15% strength by weightaqueous dispersion of the following composition: 58.04%hydroxypropylmethylcellulose (HPMC) with a viscosity of 6 mPas, 5.76%HPMC with a viscosity of 15 mPas, 5.76% hydroxypropylcellulose, 11.16%talc, 9% polyethylene glycol (PEG) 400, 1.61% PEG 6000, 8.18% titaniumdioxide, 0.19% red iron oxide, 0.15% highly disperse silica, 0.15%sodium docusate (% in each case % by weight). Coating took place in aknown manner by spraying in a coating pan.

The density was determined in liquid helium using an ultrapycnometer1000 supplied by Quantachrome Corp.

EXAMPLE 1

PVP K 30 55.07% by weight Copolyvidone* K28 10.89% by weight Na₂CO₃anhydrous (DAB) 10.00% by weight Ibuprofen 23.53% by weight Highlydisperse silica  0.51% by weight (*Copolymer of 60% by weightvinylpyrrolidone and 40% by weight vinyl acetate)

Tablet weight: 850 mg without coating, coating 15 mg, Ibuprofen dose 200mg,

Release after 10 min 100%

Density of the uncoated tablet core 1.573 g/cm³

EXAMPLE 2

PVP K 30 55.50% by weight Na₂CO₃, anhydrous 12.00% by weight Ibuprofen32.00% by weight Highly disperse silica  0.5% by weight

Tablet weight: 650 mg, coating 15 mg,

Ibuprofen dose 200 mg

Release after 10 min 100%

Density of the uncoated tablet core 1.841 g/cm³

EXAMPLE 3

PVP K30 41.00% by weight Na₂CO₃ anhydrous 12.00% by weight Ibuprofen47.00% by weight

Tablet weight: 850 mg without coating

Ibuprofen dose 400 mg

Determination of the Pharmacokinetic Parameters

The study was carried out with a single dose (200 mg) with triplecrossover on healthy men.

A drug form from Example 1 was administered. For comparison, acommercially obtainable ibuprofen lysinate (Dolormin® film-coatedtablets, 342 mg of ibuprofen D,L-lysine salt, equivalent to 200 mg ofibuprofen) was administered.

TABLE Pharmacokinetic parameters Example 1 Dolormin AUC [mg*h/L] 62.7857.41 C_(max) [mg/L] 22.77 23.19 AUC_(0-1h) [mg*h/L] 15.23 15.55 t_(max)[h] 0.50 0.50

The geometric mean is indicated in each case (n=12).

FIG. 1 depicts the blood plasma plot over a period of 12 hours. This isa plot of the plasma concentration [mg/L] against the time [h] asgeometric mean, n=12.

-□- Ibuprofen 200 mg film-coated tablet of Example 1

. . . O . . . Dolormin film-coated tablet

There is very substantial identity of the plots.

In addition, the fracture surface of an uncoated tablet of Example 1 wasexamined under the electron microscope. A metal-coated fracture surfacewas examined.

There were pores open to the fracture surface. Closed pores were alsoevident as small circular depressions.

We claim:
 1. A fast-acting analgesic drug form having a release rate ofactive ingredient of at least 95% after 10 minutes (USP 23) comprisingas analgesic substance ibuprofen in an adjuvant matrix, having a porousstructure and a density of greater than 1 and up to 2.5 g/cm³.
 2. Ananalgesic as claimed in claim 1, having a density of from 1.4 to 1.9g/cm³.
 3. An analgesic as claimed in claim 1, comprising as matrixadjuvant at least one melt-processable polymeric binder.
 4. An analgesicas claimed in claim 3, comprising as polymeric binder a homo- orcopolymer of N-vinylpyrrolidone.
 5. An analgesic as claimed in claim 1,obtainable by application of shear forces and extrusion of a mixture ofibuprofen and the matrix adjuvants.
 6. An analgesic as claimed in claim1, obtainable by use of alkali metal or alkaline earth metal carbonatesas matrix adjuvants.
 7. An analgesic as claimed in claim 1, comprisingibuprofen as racemate.
 8. A process for producing an analgesic asclaimed in claim 1, by mixing the analgesic substance with the matrixadjuvants with application of shear forces and extrusion through a diewith subsequent shaping, wherein the plasticized mixture is exposed to avacuum before extrusion through the die.
 9. An analgesic as claimed inclaim 1 having pore diameters of from 10 to 300 μm.
 10. An analgesic asclaimed in claim 9 having an average pore diameter of 80 μm.